It is well known that the neurotransmitters, dopamine (DA), norepinephrine (NE), and serotonin (5-HT), regulate a number of biological processes and that decreased levels of DA, NE, and 5-HT are associated with a number of neurological disorders and their physical manifestations. Significant effort has been expended on devising methods for adjusting the levels of these neurotransmitters in order to produce a desired pharmacological effect. Preventing the reuptake of these neurotransmitters in any combination of one, two, or all three of them is likely to be effective in treating these disorders. Targeting the dopamine transporter (DAT), norepinephrine transporter (NET), and the serotonin transporter (SERT) proteins has proven to be an effective way of increasing the levels of the respective monoamines.
Methylphenidate, currently used for the treatment of attention deficit-hyperactivity disorder, is known to be selective for inhibition of the DAT. Also, U.S. Pat. No. 5,444,070 discloses selective inhibitors of the dopamine reuptake as treatments for Parkinson's disease, drug addiction or abuse including cocaine and amphetamines.
Selective norepinephrine reuptake inhibitors (NARI) have also been disclosed. U.S. Pat. No. 6,352,986 describes methods of treating attention deficit-hyperactivity disorder (ADHD), addictive disorders, and psychoactive substance use disorders with Reboxetine. Also, Atomoxetine (Strattera®) is currently marketed as a selective NET reuptake inhibitor for ADHD.
The use of selective serotonin reuptake inhibitors (SSRI) has been shown to be effective in treating depressive disorders. Sertraline, Citalopram, and Paroxetine are well known examples of SSRIs used to treat disorders, such as depression, obsessive compulsive disorder, and panic attacks. There are several known difficulties with the SSRI class of therapeutics, including the slow onset of action, unwanted side effects, and the existence of a significant subset of the population that is not responsive to SSRI therapy.
Selective inhibitors of DAT, NET, and SERT reuptake may also be co-administered with each other or with other drugs. U.S. Pat. No. 5,532,244 discloses the use of serotonin reuptake inhibitors in combination with a serotonin 1A antagonist for the treatment of obsessive-compulsive disorder, depression, and obesity. The use of a serotonin or norepinephrine reuptake inhibitor in combination with a neurokinin-1 receptor antagonist has been disclosed in U.S. Pat. No. 6,121,261 for the treatment of ADHD. U.S. Pat. No. 4,843,071 discloses the use of a norepinephrine reuptake inhibitor in combination with a norepinephrine precursor in the treatment of obesity, drug abuse, or narcolepsy. U.S. Pat. No. 6,596,741 discloses the use of a NE, DA, or 5-HT inhibitor with either a neurokinin-1 receptor antagonist or a serotonin-1A antagonist for the treatment of a wide variety of conditions.
Also advantageous is the use of compounds that inhibit one or more of the neurotransmitters at the same time. The antidepressant qualities of the dual NET and SERT reuptake inhibitor duloxetine is disclosed in European Patent No. EP 273658. Venlafaxine is disclosed in U.S. Pat. No. 4,535,186 as a reuptake inhibitor of both NE and 5-HT for the treatment of depressive disorders. U.S. Pat. No. 6,635,675 discloses the use of the dual NE and 5-HT reuptake inhibitor milnacipran for the treatment of chronic fatigue syndrome and fibromyalgia syndrome. In addition, dual NE and 5-HT reuptake inhibitors are also disclosed in U.S. Pat. No. 6,136,083 for the treatment of depression. It is also recognized that compounds which inhibit the reuptake of NE, DA, and 5-HT in varying ratios not specifically mentioned here would also be advantageous.
Treating illnesses by inhibiting the reuptake of all three of the monoamines either through combination therapy or “triple inhibitors” may have clinical benefit as well. Rationale for inclusion of a dopamine enhancing component in anti-depressant therapy includes observed deficits in dopaminergic function, the success of combination therapy with dopamine agonists and traditional anti-depressants, and an increased sensitivity in dopamine receptors due to chronic anti-depressant administration (Skolnick et al., Life Sciences, 73:3175-3179 (2003)). Combination therapy with an SSRI and a noradrenaline and dopamine reuptake inhibitor was shown to be more efficacious in patients with treatment-resistant depression (Lam et al, J. Clin. Psychiatry, 65(3):337-340 (2004)). Another study using a combination of a serotonin and norepinephrine reuptake inhibitor with a norepinephrine and dopamine reuptake inhibitor reported a significant decrease in depressive symptoms in patients with refractory major depressive disorder who had failed to respond previously to either agent alone (Papkostas, G. I., Depression and Anxiety, 23:178-181 (2006)). In addition, the combination of bupropion-SR with either SSRIs or norepinephrine and dopamine reuptake inhibitors was found to induce less sexual dysfunction than monotherapy (Kennedy et al, J. Clin. Psychiatry, 63(3):181-186 (2002)). As such, inhibitory activity against DA reuptake, in addition to NE and 5-HT reuptake, is expected to provide a more rapid onset of anti-depressant effect than other mixed inhibitors which are selective for NET and SERT over DAT. PCT International Publication Nos. WO 03/101453 and WO 97/30997 disclose a class of compounds which are active against all three monoamine transporters. Also, PCT International Patent Publication No. WO 03/049736 discloses a series of 4-substituted piperidines, each of which displays similar activity against DA, NE, and 5-HT transporters. Bicyclo[2.2.1]heptanes (Axford et al., Bioorg. Med. Chem. Lett., 13:3277-3280 (2003)) and azabicyclo[3.1.0]hexanes (Skolnick et al., Eur. J. Pharm., 461:99-104 (2003)) are also described as triple inhibitors of the three monoamine transporters.
U.S. Pat. No. 3,225,031 discloses phenyl tetrahydrobenzazepines of formula 1 (where R is a member of the group consisting of H, lower alkyl and phenyl-lower alkyl, and X is a member of the group consisting of H and methyl), which are said to be useful in elevating mood or establishing wakefulness. At higher doses, these compounds are said to elicit analgesic response, while their non-toxic quaternary salts are said to be useful as anticholinergic or parasympathetic blocking agents.

Phenyl tetrahydrobenzazepines of formula 2, (where R is a member of the group consisting of H, lower alkyl, lower alkenyl, and isocyclic-lower alkyl having 3-6 cyclic carbon atoms, R1 is lower alkyl, and X is a member of the group consisting of hydrogen and lower alkyl) described in U.S. Pat. No. 3,242,164 are said to possess analgesic activity. The compound of formula 2 possesses an ester functionality at the 5-position of the 2,3,4,5-tetrahydro-1H-benzo[c]azepine core.

Japanese Patent Application No. 590113761 discloses the use of phenyl tetrahydrobenzazepines of formula 3 (where R represents a halogen, a hydroxy group, a nitro group, or an amino group) as analgesics.

Compounds, 8-(methylthio)-5-phenyl-2,3,4,5-tetrahydro-1H-benzo[c]azepine (4), 6-(methylthio)-5-phenyl-2,3,4,5-tetrahydro-1H-benzo[c]azepine (5), and 2,3,4,5-tetrahydro-1H-benzo[c]azepine (6), are described in Euerby et al., Synth. Commun., 16:779-784 (1986) and in Euerby et al., J. Chem. Research (S), pp. 40-41 (1987) as substrates (4 and 5) and product (6) in reductive desulphurization of thioethers with nickel bromide. No usage or activity was reported in those references.

PCT International Patent Publication No. WO 2001/003680 discloses compounds of formula 7 (where C is a carbon; N is a nitrogen; H is a hydrogen; A1, A2, A3, A4, A5, and A6 are independently alkyl, O, S, or —NH; m and n (for each individual A group) are independently 0 or 1; p, q, and 1 are independently 0, 1, or 2; R7, R8, R9, R10, R11, R12, and each R14 are independently hydrogen, alkyl, alicyclyl, heterocyclyl, or aryl, each R13 is independently hydrogen, alkyl, alicyclyl, heterocycyl, aryl, or an anionic group, and adjacent R groups (e.g., R7 and R8) may form an unsubstituted or substituted cyclic or heterocyclic ring) as inhibitors of islet amyloid polypeptide (IAPP) associated amyloidosis. These compounds are suggested for use in disorders in which such amyloid deposition occurs, such as diabetes.

U.S. Pat. No. 5,607,939 discloses compounds of formula 8 (where ring A represents a benzene ring; Ar represents an aromatic group; R1 and R2 independently represent hydrogen, acyl, or hydrocarbon group, or R1 and R2 taken together with the adjacent nitrogen atom represent a nitrogen-containing heterocyclic group; m represents an integer of 1 to 6; n represents an integer of 2 to 3;  represents a single bond or a double bond; X stands for —O— or —NR3— in which R3 represents hydrogen, acyl, or hydrocarbon group where  is a single bond or ═N— where  is a double bond) as gonadotropin-releasing hormone (GnRH) receptor antagonists and suggests their use in acute and chronic CNS disorders, such as dysmnesia. This reference discloses 5-aryl 2,3,4,5-tetrahydro-1H-benzo[c]azepines with particular cyclic aminoalkyl groups at the 5-position of the 2,3,4,5-tetrahydro-1H-benzo[c]azepines.

Great Britain Patent No. GB 2271566 discloses compounds of formula 9 (where n is 0-3; p is 1-2; q is 1-2; X is CH2, O, or N—R1, and R1 is H, C1-4 alkyl or C3-5 cycloalkyl; R is (a) C1-6 alkyl, (b) C1-6 alkoxy, (c) hydroxyl, (d) halogen, (e) CN, (f) NO2, (g) NHSO2CH3, or (h) COOH; G is H or R) as HIV integrase inhibitors.

PCT International Patent Publication No. WO 99/045013 discloses compounds of formula 10 (where A together with the double bond of formula 10 forms a cyclic system selected from the group consisting of benzene, thiophene, furan, pyridine, pyrimidine, pyrazine, pyridazine, pyrrole, indole, pyrazole, imidazole, oxazole, isoxazole, and thiazole; R2 is an optionally substituted C1-6-alkyl, optionally substituted heterocyclyl; R1 is heteroaryl, optionally substituted; R4 and R5 are independently hydrogen, halogen, perhalomethyl, optionally substituted C1-6-alkyl, hydroxy, optionally substituted C1-6-alkoxy, nitro, cyano, amino, optionally substituted mono- or optionally substituted di-C1-6-alkylamino, acylamino, C1-6-alkoxycarbonyl, carboxy, or carbamoyl; m is 0, 1, or 2; n is 0, 1, or 2) for the treatment or prevention of diseases of the endocrinological system.

Brooks et al., Journal of Chemical Society [Section] C: Organic, pp. 625-627 (1969) describes the synthesis of compound of formula 11 and formula 12 via acid catalyzed ring-closure method. No biological activity of these compounds is reported in the above-mentioned reference. U.S. Pat. Nos. 3,655,651 and 3,642,993 disclose a single compound of formula 11 and suggest its sedative-hypnotic effect.


Arany et al., J. Chem. Soc, Perkin Trans. I: 2605-2608 (1999) and Arany et al., Tetrahedron Letters 39:3267-3268 (1998) describe compounds of formula 13 as products of electrocyclisation of azomethine ylides. No biological activity of these compounds is reported in the above mentioned references.

Gast et al., Helvetica Chimica Acta, 60(5):1644-1649 (1977) describes compounds of formula 14 as products of the cyclization of 2-(β-styryl)benzylamine derivatives. No biological activity is disclosed in the above mentioned reference.

Toda et al., Bioorganic and Medicinal Chemistry, 11 (20):4389-4415 (2003) describes compounds of formula 15 as dual inhibitors of acetylcholinesterase and serotonin transporter and potential agents for Alzheimer's disease. The IC50s for the serotonin transporter for the three compounds of formula 15 are reported to be >1000 nM in the above mentioned reference.

There is still a large need for compounds that block the reuptake of norepinephrine, dopamine, and serotonin and treat various neurological and psychological disorders.
The present invention is directed to achieving this objective.